Stefan H. M. Gorissen

Anabolic resistance of muscle protein synthesis with aging.

Aging has been associated with a reduced muscle protein synthetic response to protein intake, termed “anabolic resistance.” Physical activity performed before protein intake increases the use of protein-derived amino acids for postprandial muscle protein accretion in senescent muscle. Thus, the level of habitual physical activity may be fundamental to maintain the anabolic responsiveness to protein intake with aging.

Aging Is Accompanied by a Blunted Muscle Protein Synthetic Response to Protein Ingestion

Purpose Progressive loss of skeletal muscle mass with aging (sarcopenia) forms a global health concern. It has been suggested that an impaired capacity to increase muscle protein synthesis rates in response to protein intake is a key contributor to sarcopenia. We assessed whether differences in post-absorptive and/or post-prandial muscle protein synthesis rates exist between large cohorts of healthy young and older men. Procedures We performed a cross-sectional, retrospective study comparing in vivo post-absorptive muscle protein synthesis rates determined with stable isotope methodologies between 34 healthy young (22±1 y) and 72 older (75±1 y) men, and post-prandial muscle protein synthesis rates between 35 healthy young (22±1 y) and 40 older (74±1 y) men. Findings Post-absorptive muscle protein synthesis rates did not differ significantly between the young and older group. Post-prandial muscle protein synthesis rates were 16% lower in the older subjects when compared with the young. Muscle protein synthesis rates were >3 fold more responsive to dietary protein ingestion in the young. Irrespective of age, there was a strong negative correlation between post-absorptive muscle protein synthesis rates and the increase in muscle protein synthesis rate following protein ingestion. Conclusions Aging is associated with the development of muscle anabolic inflexibility which represents a key physiological mechanism underpinning sarcopenia.

Carbohydrate Coingestion Delays Dietary Protein Digestion and Absorption but Does Not Modulate Postprandial Muscle Protein Accretion

BACKGROUND Dietary protein digestion and absorption is an important factor modulating muscle protein accretion. However, there are few data available on the effects of coingesting other macronutrients with protein on digestion and absorption kinetics and the subsequent muscle protein synthetic response. OBJECTIVE The objective of the study was to determine the impact of carbohydrate coingestion with protein on dietary protein digestion and absorption and muscle protein accretion in healthy young and older men. DESIGN Twenty-four healthy young (aged 21± 1 y, body mass index 21.8 ±0.5 kg/m(2)) and 25 older (aged 75 ± 1 y, body mass index 25.4 ± 0.6 kg/m(2)) men received a primed continuous L-[ring-(2)H5]-phenylalanine and L-[ring-3,5-(2)H2]-tyrosine infusion and ingested 20 g intrinsically L-[1-(13)C]-phenylalanine-labeled protein with (Pro+CHO) or without (Pro) 60 g carbohydrate. Plasma samples and muscle biopsies were collected in a postabsorptive and postprandial state. RESULTS Carbohydrate coingestion delayed the appearance of exogenous phenylalanine in the circulation (P = .001). Dietary protein-derived phenylalanine availability over the 5-hour postprandial period was lower in the older (62 ± 2%) when compared with the young subjects (74 ± 2%; P = .007), with no differences between conditions (P = .20). Carbohydrate coingestion did not modulate postprandial muscle protein synthesis rates (0.035 ± 0.003 vs 0.043 ± 0.004 and 0.033 ± 0.002 vs 0.035 ± 0.003%/h after Pro vs Pro+CHO in the young and older group, respectively). In accordance, no differences in muscle protein-bound L-[1-(13)C]-phenylalanine enrichments were observed between conditions (0.020 ± 0.002 vs 0.020 ± 0.002 and 0.019 ± 0.003 vs 0.022 ± 0.004 mole percent excess after Pro vs Pro+CHO in the young and older subjects, respectively). CONCLUSION Carbohydrate coingestion with protein delays dietary protein digestion and absorption but does not modulate postprandial muscle protein accretion in healthy young or older men.

Differences in postprandial protein handling after beef compared with milk ingestion during postexercise recovery: a randomized controlled trial

BACKGROUND Protein consumed after resistance exercise increases postexercise muscle protein synthesis rates. To date, dairy protein has been studied extensively, with little known about the capacity of other protein-dense foods to augment postexercise muscle protein synthesis rates. OBJECTIVE We aimed to compare protein digestion and absorption kinetics, postprandial amino acid availability, anabolic signaling, and the subsequent myofibrillar protein synthetic response after the ingestion of milk compared with beef during recovery from resistance-type exercise. DESIGN In crossover trials, 12 healthy young men performed a single bout of resistance exercise. Immediately after cessation of exercise, participants ingested 30 g protein by consuming isonitrogenous amounts of intrinsically l-[1-(13)C]phenylalanine-labeled beef or milk. Blood and muscle biopsy samples were collected at rest and after exercise during primed continuous infusions of l-[ring-(2)H5]phenylalanine and l-[ring-3,5-(2)H2]tyrosine to assess protein digestion and absorption kinetics, plasma amino acid availability, anabolic signaling, and subsequent myofibrillar protein synthesis rates in vivo in young men. RESULTS Beef protein-derived phenylalanine appeared more rapidly in circulation compared with milk ingestion (P < 0.001). The availability of phenylalanine during the 5-h postexercise period tended to be higher after beef (64% ± 3%) ingestion than after milk ingestion (57% ± 3%; P = 0.08). Both beef and milk ingestion were followed by an increase in the phosphorylation of mammalian target of rapamycin complex 1 and 70-kDa S6 protein kinase 1 during postexercise recovery. Milk ingestion increased myofibrillar protein synthesis rates to a greater extent than did beef ingestion during the 0- to 2-h postexercise phase (P = 0.013). However, the increase in myofibrillar protein synthesis rates did not differ between milk and beef ingestion during the entire 0- to 5-h postexercise phase (P = 0.114). CONCLUSIONS Both milk and beef ingestion augment the postexercise myofibrillar protein synthetic response in young men, with a stronger stimulation of myofibrillar protein synthesis during the early postprandial stage after milk ingestion. This trial was registered at www.clinicaltrials.gov as NCT01578590.

The use of doubly labeled milk protein to measure postprandial muscle protein synthesis rates in vivo in humans

We aimed to determine the impact of precursor pool dilution on the assessment of postprandial myofibrillar protein synthesis rates (MPS). A Holstein dairy cow was infused with large amounts of L-[1-(13)C]phenylalanine and L-[1-(13)C]leucine, and the milk was collected and fractionated. The enrichment levels in the casein were 38.7 and 9.3 mole percent excess, respectively. In a subsequent human experiment, 11 older men (age: 71 ± 1 y, body mass index: 26 ± 0.1 kg·m(-2)) received a primed constant infusion of L-[ring-(2)H5]phenylalanine and L-[1-(13)C]leucine. Blood and muscle samples were collected before and after the ingestion of 20-g doubly labeled casein to assess postprandial MPS based on the 1) constant tracer infusion of L-[ring-(2)H5]phenylalanine, 2) ingestion of intrinsically L-[1-(13)C]phenylalanine-labeled casein, and 3) constant infusion of L-[1-(13)C]leucine in combination with the ingestion of intrinsically L-[1-(13)C]leucine-labeled casein. Postprandial MPS was increased (P < 0.05) after protein ingestion (∼70% above postabsorptive values) based on the L-[1-(13)C]leucine tracer. There was no significant stimulation of postprandial MPS (∼27% above postabsorptive values) when the calculated fractional synthesis rate was based on the L-[ring-(2)H5]phenylalanine (P = 0.2). Comparisons of postprandial MPS based on the primed continuous infusion of L-[1-(13)C]leucine or the ingestion of intrinsically L-[1-(13)C]phenylalanine-labeled casein protein demonstrated differences compared with the primed continuous infusion of L-[ring-(2)H5]phenylalanine (P > 0.05). Our findings confirm that the postprandial MPS assessed using the primed continuous tracer infusion approach may differ if tracer steady-state conditions in the precursor pools are perturbed. The use of intrinsically doubly labeled protein provides a method to study the metabolic fate of the ingested protein and the subsequent postprandial MPS response.

Ingestion of Wheat Protein Increases In Vivo Muscle Protein Synthesis Rates in Healthy Older Men in a Randomized Trial

BACKGROUND Muscle mass maintenance is largely regulated by basal muscle protein synthesis and the capacity to stimulate muscle protein synthesis after food intake. The postprandial muscle protein synthetic response is modulated by the amount, source, and type of protein consumed. It has been suggested that plant-based proteins are less potent in stimulating postprandial muscle protein synthesis than animal-derived proteins. However, few data support this contention. OBJECTIVE We aimed to assess postprandial plasma amino acid concentrations and muscle protein synthesis rates after the ingestion of a substantial 35-g bolus of wheat protein hydrolysate compared with casein and whey protein. METHODS Sixty healthy older men [mean ± SEM age: 71 ± 1 y; body mass index (in kg/m(2)): 25.3 ± 0.3] received a primed continuous infusion of l-[ring-(13)C6]-phenylalanine and ingested 35 g wheat protein (n = 12), 35 g wheat protein hydrolysate (WPH-35; n = 12), 35 g micellar casein (MCas-35; n = 12), 35 g whey protein (Whey-35; n = 12), or 60 g wheat protein hydrolysate (WPH-60; n = 12). Plasma and muscle samples were collected at regular intervals. RESULTS The postprandial increase in plasma essential amino acid concentrations was greater after ingesting Whey-35 (2.23 ± 0.07 mM) than after MCas-35 (1.53 ± 0.08 mM) and WPH-35 (1.50 ± 0.04 mM) (P < 0.01). Myofibrillar protein synthesis rates increased after ingesting MCas-35 (P < 0.01) and were higher after ingesting MCas-35 (0.050% ± 0.005%/h) than after WPH-35 (0.032% ± 0.004%/h) (P = 0.03). The postprandial increase in plasma leucine concentrations was greater after ingesting Whey-35 than after WPH-60 (peak value: 580 ± 18 compared with 378 ± 10 μM, respectively; P < 0.01), despite similar leucine contents (4.4 g leucine). Nevertheless, the ingestion of WPH-60 increased myofibrillar protein synthesis rates above basal rates (0.049% ± 0.007%/h; P = 0.02). CONCLUSIONS The myofibrillar protein synthetic response to the ingestion of 35 g casein is greater than after an equal amount of wheat protein. Ingesting a larger amount of wheat protein (i.e., 60 g) substantially increases myofibrillar protein synthesis rates in healthy older men. This trial was registered at clinicaltrials.gov as NCT01952639.

The muscle protein synthetic response to food ingestion

Preservation of skeletal muscle mass is of great importance for maintaining both metabolic health and functional capacity. Muscle mass maintenance is regulated by the balance between muscle protein breakdown and synthesis rates. Both muscle protein breakdown and synthesis rates have been shown to be highly responsive to physical activity and food intake. Food intake, and protein ingestion in particular, directly stimulates muscle protein synthesis rates. The postprandial muscle protein synthetic response to feeding is regulated on a number of levels, including dietary protein digestion and amino acid absorption, splanchnic amino acid retention, postprandial insulin release, skeletal muscle tissue perfusion, amino acid uptake by muscle, and intramyocellular signaling. The postprandial muscle protein synthetic response to feeding is blunted in many conditions characterized by skeletal muscle loss, such as aging and muscle disuse. Therefore, it is important to define food characteristics that modulate postprandial muscle protein synthesis. Previous work has shown that the muscle protein synthetic response to feeding can be modulated by changing the amount of protein ingested, the source of dietary protein, as well as the timing of protein consumption. Most of this work has studied the postprandial response to the ingestion of isolated protein sources. Only few studies have investigated the postprandial muscle protein synthetic response to the ingestion of protein dense foods, such as dairy and meat. The current review will focus on the capacity of proteins and protein dense food products to stimulate postprandial muscle protein synthesis and identifies food characteristics that may modulate the anabolic properties.

Habituation to low or high protein intake does not modulate basal or postprandial muscle protein synthesis rates: a randomized trial

BACKGROUND Muscle mass maintenance is largely regulated by basal muscle protein synthesis rates and the ability to increase muscle protein synthesis after protein ingestion. To our knowledge, no previous studies have evaluated the impact of habituation to either low protein intake (LOW PRO) or high protein intake (HIGH PRO) on the postprandial muscle protein synthetic response. OBJECTIVE We assessed the impact of LOW PRO compared with HIGH PRO on basal and postprandial muscle protein synthesis rates after the ingestion of 25 g whey protein. DESIGN Twenty-four healthy, older men [age: 62 ± 1 y; body mass index (in kg/m2): 25.9 ± 0.4 (mean ± SEM)] participated in a parallel-group randomized trial in which they adapted to either a LOW PRO diet (0.7 g · kg-1 · d-1; n = 12) or a HIGH PRO diet (1.5 g · kg-1 · d-1; n = 12) for 14 d. On day 15, participants received primed continuous l-[ring-2H5]-phenylalanine and l-[1-13C]-leucine infusions and ingested 25 g intrinsically l-[1-13C]-phenylalanine- and l-[1-13C]-leucine-labeled whey protein. Muscle biopsies and blood samples were collected to assess muscle protein synthesis rates as well as dietary protein digestion and absorption kinetics. RESULTS Plasma leucine concentrations and exogenous phenylalanine appearance rates increased after protein ingestion (P < 0.01) with no differences between treatments (P > 0.05). Plasma exogenous phenylalanine availability over the 5-h postprandial period was greater after LOW PRO than after HIGH PRO (61% ± 1% compared with 56% ± 2%, respectively; P < 0.05). Muscle protein synthesis rates increased from 0.031% ± 0.004% compared with 0.039% ± 0.007%/h in the fasted state to 0.062% ± 0.005% compared with 0.057% ± 0.005%/h in the postprandial state after LOW PRO compared with HIGH PRO, respectively (P < 0.01), with no differences between treatments (P = 0.25). CONCLUSION Habituation to LOW PRO (0.7 g · kg-1 · d-1) compared with HIGH PRO (1.5 g · kg-1 · d-1) augments the postprandial availability of dietary protein-derived amino acids in the circulation and does not lower basal muscle protein synthesis rates or increase postprandial muscle protein synthesis rates after ingestion of 25 g protein in older men. This trial was registered at clinicaltrials.gov as NCT01986842.

Postprandial Protein Handling Is Not Impaired in Type 2 Diabetes Patients When Compared With Normoglycemic Controls

CONTEXT The progressive loss of muscle mass with aging is accelerated in type 2 diabetes patients. It has been suggested that this is attributed to a blunted muscle protein synthetic response to food intake. OBJECTIVE The objective of the study was to test the hypothesis that the muscle protein synthetic response to protein ingestion is impaired in older type 2 diabetes patients when compared with healthy, normoglycemic controls. DESIGN A clinical intervention study with two parallel groups was conducted between August 2011 and July 2012. SETTING The study was conducted at the research unit of Maastricht University, The Netherlands. Intervention, Participants, and Main Outcome Measures: Eleven older type 2 diabetes males [diabetes; age 71 ± 1 y, body mass index (BMI) 26.2 ± 0.5 kg/m(2)] and 12 age- and BMI-matched normoglycemic controls (control; age 74 ± 1 y, BMI 24.8 ± 1.1 kg/m(2)) participated in an experiment in which they ingested 20 g intrinsically L-[1-(13)C]phenylalanine-labeled protein. Continuous iv L-[ring-(2)H5]phenylalanine infusion was applied, and blood and muscle samples were obtained to assess amino acid kinetics and muscle protein synthesis rates in the postabsorptive and postprandial state. RESULTS Plasma insulin concentrations increased after protein ingestion in both groups, with a greater rise in the diabetes group. Postabsorptive and postprandial muscle protein synthesis rates did not differ between groups and averaged 0.029 ± 0.003 vs 0.029 ± 0.003%/h(1) and 0.031 ± 0.002 vs 0.033 ± 0.002%/h(1) in the diabetes versus control group, respectively. Postprandial L-[1-(13)C]phenylalanine incorporation into muscle protein did not differ between groups (0.018 ± 0.001 vs 0.019 ± 0.002 mole percent excess, respectively). CONCLUSIONS Postabsorptive muscle protein synthesis and postprandial protein handling is not impaired in older individuals with type 2 diabetes when compared with age-matched, normoglycemic controls.

Presleep protein ingestion does not compromise the muscle protein synthetic response to protein ingested the following morning

Protein ingestion before sleep augments postexercise muscle protein synthesis during overnight recovery. It is unknown whether postexercise and presleep protein consumption modulates postprandial protein handling and myofibrillar protein synthetic responses the following morning. Sixteen healthy young (24 ± 1 yr) men performed unilateral resistance-type exercise (contralateral leg acting as a resting control) at 2000. Participants ingested 20 g of protein immediately after exercise plus 60 g of protein presleep (PRO group; n = 8) or equivalent boluses of carbohydrate (CON; n = 8). The subsequent morning participants received primed, continuous infusions of l-[ring-2H5]phenylalanine and l-[1-13C]leucine combined with ingestion of 20 g intrinsically l-[1-13C]phenylalanine- and l-[1-13C]leucine-labeled protein to assess postprandial protein handling and myofibrillar protein synthesis in the rested and exercised leg in CON and PRO. Exercise increased postabsorptive myofibrillar protein synthesis rates the subsequent day (P < 0.001), with no differences between CON and PRO. Protein ingested in the morning increased myofibrillar protein synthesis in both the exercised and rested leg (P < 0.01), with no differences between treatments. Myofibrillar protein bound l-[1-13C]phenylalanine enrichments were greater in the exercised (0.016 ± 0.002 and 0.015 ± 0.002 MPE in CON and PRO, respectively) vs. rested (0.010 ± 0.002 and 0.009 ± 0.002 MPE in CON and PRO, respectively) leg (P < 0.05), with no differences between treatments (P > 0.05). The additive effects of resistance-type exercise and protein ingestion on myofibrillar protein synthesis persist for more than 12 h after exercise and are not modulated by protein consumption during acute postexercise recovery. This work provides evidence of an extended window of opportunity where presleep protein supplementation can be an effective nutrient timing strategy to optimize skeletal muscle reconditioning.